Diagnostic imaging employing agents capable of enhancing the images obtainable with different imaging techniques (known as “contrast agents” or “image enhancing agents”) has become a widely adopted practice in the diagnostic field.
Rapid development of contrast agents in recent years has generated a number of different formulations, which are useful in contrast-enhanced imaging of organs and tissue of the human or animal body.
A class of contrast agents, particularly useful for ultrasound contrast imaging, includes suspensions of gas bubbles of nano- and/or micro-metric size dispersed in an aqueous medium. Of particular interest are those formulations where the gas bubbles are stabilized, for example by using emulsifiers, oils, thickeners or sugars, or by entrapping or encapsulating the gas or a precursor thereof in a variety of systems. These stabilized gas bubbles are generally referred to in the art with various terminologies, such as, for instance, “microvesicles”, “microspheres”, “microbubbles”, “microcapsules” or “microballoons”. In the present description and claims, the term “microvesicles” is used to identify any of the above described stabilized gas-bubbles.
Other contrast agents include iodinated products (such as iopamidol or iomeprol), which are widely employed in X-ray contrast analysis, in particular computer tomography (CT) X-ray, whilst compounds containing paramagnetic ions (such as ProHance® or MultiHance®, Bracco Imaging), are widely employed in MRI analysis. The active (X-ray or MRI) imaging agent can advantageously be incorporated in liposome structures (see e.g. Ref. 1 or Ref. 2).
Gas-filled microvesicles may include in their formulation a polymer, in particular a hydrophilic polymer (e.g. polyethyleneglycol, PEG), which has been found useful, for instance, for reducing immunogenicity, improve biocompatibility, reduce receptor mediated uptake by the reticuloendothelial system (RES) and/or increase the serum half-life of the contrast agent. For similar reasons, polymers, such as PEG, have also been included in the formulation of liposomes employed as carriers for contrast or therapeutic agents.
More recently, gas-filled microvesicles have been modified with suitable target-specific components, capable of selectively binding the microvesicles to a desired organ or tissue.
For instance, microvesicles or liposomes can be associated (e.g. by inclusion in their boundary envelope) with specific components which are capable of binding to a determined target or region within a patient's body (known as “targeting ligands”), so to selectively enhance the imaging of said target or region.
Examples of targeting ligands include, for instance, peptides, proteins or antibodies, capable of binding to a specific organ or tissue such as, for instance, angiogenic inflammatory or thrombosed tissue.
For instance, the structure of a microvesicle or of a liposome can be modified by binding the targeting ligand to suitable molecules which are employed for the formation of the microvesicle's or liposome's envelope. The targeting moiety can be directly linked to the envelope-forming molecule or through a suitable spacer. This methodology thus typically entails a modification of the components forming the microvesicle or liposome envelope, to allow the binding thereof to the desired targeting moiety.
The Applicant has now found a new method where the targeting ligand is associated with a polymer-containing liposome or gas-filled microvesicle by means of an antibody capable of specifically recognising said polymeric component comprised in said liposome or microvesicle.